Disease relevance of Cldn11

• Elucidating the molecular mechanisms underlying TNF-alpha regulation of MBP gene expression provides new scientific bases for the development of therapy against oligodendrocyte-specific and myelin-related disorders such as multiple sclerosis [1].
• The outer surface protein (Osp) A of Borrelia burgdorferi is the first Lyme antigen to be tested in a vaccine for humans [2].
• We have generated transgenic mice expressing the entire HIV-1 genome under the regulation of an oligodendrocyte-specific promoter [3].
• Spirochetes expressing Osp A could also be detected within the first 2 wk of infection, but not at 30 d [4].
• The murine immune response to Borrelia burgdorferi (Bb), the etiologic agent of Lyme disease, is characterized by the development of antibodies reactive with the outer surface protein (Osp) A [5].

High impact information on Cldn11

• Our results demonstrate that OSP is the mediator of parallel-array tight junction strands and distinguishes this protein from other intrinsic membrane proteins in tight junctions [6].
• Oligodendrocyte-specific protein (OSP)/claudin-11 is a recently identified transmembrane protein found in CNS myelin and testis with unknown function [6].
• Herein we demonstrate that Osp null mice exhibit both neurological and reproductive deficits: CNS nerve conduction is slowed, hindlimb weakness is conspicuous, and males are sterile [6].
• To address this issue directly, transgenic mice were generated that expressed the cDNA of murine IFN-gamma in the central nervous system by using an oligodendrocyte-specific promoter [7].
• In contrast, antibodies to Osp C were prominent, even though on cultured spirochetes Osp C mRNA and protein expression could not be detected by reverse transcription polymerase chain reaction (RT-PCR) or indirect immunofluorescence, respectively [4].

Biological context of Cldn11

• Indeed, OSP is expressed early in fetal development in Sertoli cells, immediately after the peak of SRY (sex-determining region, Y gene) expression, but just before that of the anti-Mullerian hormone [8].
• Since both OSP/claudin-11 and PLP are abundant in myelin and have similar structures, the mild phenotypes of the knockout mice are likely due to compensatory mechanisms [9].
• Taken together, these data suggest that Zfp488 functions as an oligodendrocyte-specific transcription co-regulator important for oligodendrocyte maturation and that zinc-finger/bHLH cooperation can serve as a mechanism for oligodendroglial differentiation [10].
• Fine mapping with fluorescence in situ hybridization placed the OSP gene at human chromosome 3q26.2-q26 [11].
• Myelin basic protein (MBP) is an oligodendrocyte-specific protein essential for oligodendrocyte morphogenesis at late stages of cell differentiation [12].

Anatomical context of Cldn11

• Indeed, using a model of purified cultured mouse Sertoli cells, we demonstrate that FSH inhibits, in a dose (ED50 = 4 ng/ml)- and time (maximal effect after 24 h)-dependent manner, the levels of OSP mRNA [8].
• Developmental and hormonal regulation of the expression of oligodendrocyte-specific protein/claudin 11 in mouse testis [8].
• Our data show that the testicular expression of OSP is dependent upon male gonad development and systemic and local signaling molecules [8].
• In the prepubertal and adult testes, an apparent decline in OSP messenger RNA (mRNA) levels was found, probably because of the increasing number of germ cells (which do not express OSP) [8].
• An OSP-specific polyclonal antibody reacted with a single 22-kd protein present in CNS myelin and oligodendrocytes [13].

Associations of Cldn11 with chemical compounds

• Oligodendrocyte-specific ceramide galactosyltransferase (CGT) expression phenotypically rescues CGT-deficient mice and demonstrates that CGT activity does not limit brain galactosylceramide level [14].
• This receptor is highly hydrophobic, contains four putative transmembrane segments, and has significant similarity to the rat androgen withdrawal apoptosis protein RVP1 and the mouse oligodendrocyte specific protein, the functions of which are unknown [15].
• Antibodies to myelin/oligodendrocyte-specific protein and myelin/oligodendrocyte glycoprotein signal distinct changes in the organization of cultured oligodendroglial membrane sheets [16].
• Regardless of culture conditions, there existed a large population of cells that resembled oligodendrocytes morphologically and coexpressed the oligodendrocyte-specific marker galactocerebroside (GalC) and the acetylcholine (ACh)-synthesizing enzyme choline acetyltransferase (ChAT) [17].
• Furthermore, B-cell mitogenic properties were also found in two distinct fractions of a phenol-chloroform-petroleum ether extract of B. burgdorferi: they consisted of a lipoprotein distinct from the outer surface proteins (Osp) A and B and glycolipid-like structures, respectively [18].

Regulatory relationships of Cldn11

• TNFalpha was also shown to inhibit OSP expression in cultured Sertoli cells [8].
• PLP expression levels of the wt control were recovered by Cre excision of the neo-selection gene after intercrossing neoS mice and oligodendrocyte-specific Cre-mice [19].
• Compared with wild-type controls, oligodendrocyte-specific SOCS3 conditional-knockout mice displayed enhanced c-fos activation and exogenous LIF-induced phosphorylation of signal transducer and activator of transcription 3 [20].
• Oligodendrocyte-specific expression of full-length PrP(C) under control of the myelin basic protein (MBP) promoter repressed leukoencephalopathy and vastly extended survival but did not prevent cerebellar granule cell (CGC) degeneration [21].

Other interactions of Cldn11

• Among the signaling molecules that control testicular OSP expression, we have identified FSH and tumor necrosis factor-alpha (TNFalpha) [8].
• OSP/claudin-11 and PLP are both tetraspan proteins concentrated in CNS myelin [9].
• Various lengths (6.5 kb to 256 bp) of the promoter region of the (classic) MBP gene directed oligodendrocyte-specific expression of the reporter gene in transgenic mice, but no expression was seen in Schwann cells [22].
• In the stria vascularis, claudin-1, -2, -3, -8, -9, -10, -12, -14 and -18 were expressed in the marginal cells, whereas the basal cells were positive only for claudin-11 [23].
• Cells were examined by double-label indirect immunofluorescence for the presence of the PLP C-terminus and either oligodendrocyte-specific surface or intracellular antigens [24].

Analytical, diagnostic and therapeutic context of Cldn11

• In situ hybridization revealed expression of this cDNA in oligodendrocytes of brain and spinal cord as well as in oligodendrocyte-enriched cultures; therefore we have named it oligodendrocyte-specific protein (OSP) cDNA [13].
• In testis, well-developed TJ strands of Sertoli cells were specifically labeled with anti-claudin-11/OSP pAb both at immunofluorescence and electron microscopic levels [25].
• By direct fluorescent staining of uncultured spirochetes ex vivo and by PCR amplification of spirochetal mRNA, we show that Osp C is indeed expressed by some spirochetes after infection in the mouse [4].
• Osp A mRNA, although present at day 14 of infection, could not be amplified by RT-PCR at day 30, suggesting that the expression of this Osp is transient [4].
• As expected, vaccination with full-length recombinant Osp A protected mice from challenge infection [5].

References